Prev: severe food allergies
Next: Is this allergic reaction or severe Asthma attack?
From: Kofi on 28 Jun 2008 22:27
I'm considering beta-glucuronidase therapy for my numerous allergies, so
I've been researching the pathways that might be involved.
Beta-glucuronidase and heparanase are on branches of the HIF-1a pathway
recently discovered to be so important for gut integrity. While
hunting, I stumbled on a paper linking heparanase and autoimmunity - in
particular I.B.D.s - and I remembered discussions about a "thick blood"
hypothesis years ago. Patients were treated with low-molecular weight
heparin for their supposed "hypercoagulation." It never made much sense
to me and I ignored it when my test results proved my clotting was
normal.

Well, now we learn that in the G.I. tract of individuals with Crohn's
and I.B.D., heparanase is upregulated - but only in the intestinal skin
(epithelial) cells and not immune cells. Heparin happens to inhibit
heparanase and provide analgesia to people with Crohn's and I.B.D.
Could it be these individuals who were helped by heparin never had a
clotting disorder but instead benefited from this recently discovered
property of heparin?

More importantly, what is heparanase doing to provoke autoimmunity and
does beta-glucuronidase interact with it to prooduce its desensitization
effects?

I would also like to point out here the involvement of protein kinase C
(PKC) with both the secretion of heparanase and the functioning of
regulatory T-cells and gap junction proteins like zonulin. I've posted
articles on PKC inhibition and leaky gut in the past. Heparanase seems
to provide yet one more link.

Recent research indicates heparanase is also involved in anagen, the
growth phase of hair follicles (perhaps via angiogenesis). This
probably explains why chronic heparin use is known to cause diffuse hair
loss.

Mod Pathol. 2007 Jan;20(1):8-14. Epub 2006 Oct 13.
�
Heparanase upregulation by colonic epithelium in inflammatory bowel
disease.
Waterman M, Ben-Izhak O, Eliakim R, Groisman G, Vlodavsky I, Ilan N.
Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel.

Heparanase is an endo-beta-D-glucuronidase capable of cleaving heparan
sulfate (HS) side chains at a limited number of sites, yielding HS
fragments of still appreciable size ( approximately 5-7 kDa). Heparanase
activity has long been detected in a number of cell types and tissues.
Importantly, heparanase activity correlated with the metastatic
potential of tumor-derived cells, attributed to enhanced cell
dissemination as a consequence of HS cleavage and remodeling of the
extracellular matrix barrier. Similarly, heparanase activity was
implicated in neovascularization, inflammation and autoimmunity,
involving migration of vascular endothelial cells and activated cells of
the immune system. The involvement of heparanase in inflammatory
processes of the gastrointestinal tract has not been examined. Here, we
utilized immunohistochemical analysis to investigate heparanase
expression in acute and chronic inflammatory conditions. Heparanase
expression was not detected in specimens derived from normal colon
tissue. In contrast, strong heparanase staining was observed in Crohn's
disease and ulcerative colitis, but not in infectious colitis.
Interestingly, heparanase staining was primarily observed in epithelial
rather than immune cells. Importantly, un-fractionated as well as low
molecular weight heparin (enoxaparin), which exhibit a strong inhibitory
activity towards heparanase, have proven efficacious in ulcerative
colitis and Crohn's disease patients, suggesting that heparanase is
actively involved in these pathologies and thus may be considered as a
target for the development of anti-inflammatory therapies.

Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't

PMID: 17041566 [PubMed - indexed for MEDLINE]

Exp Dermatol. 2008 Jun 14;

Heparanase 1: a key participant of inner root sheath differentiation
program and hair follicle homeostasis.
Malgouries S, Donovan M, Thibaut S, Bernard BA.
L'Oreal Recherche, Clichy, France.

Heparanase is a heparan sulphate endo-glycosidase which was previously
detected in the outer root sheath of murine hair follicles. Heparanase
overexpression was reported to improve mouse hair (re)growth. In this
study, we investigated its involvement in human hair biology.
Immunofluorescence detection was used to explore heparanase distribution
in both anagen and catagen hair follicles. Heparanase functionality was
assessed in in vitro cultured hair follicles, in the presence of a
heparanase activity inhibitor. Our results showed that heparanase
expression was (i) primarily located in the inner root sheath (IRS) of
human hair follicle, and there (ii) restricted to anagen phase.
Furthermore, inhibition of heparanase in in vitro cultured hair
follicles induced a catagen-like process. Hair shaft retreat upward was
accompanied by a decrease in Ki67-positive cells, the formation of an
epithelial strand as evidenced by K14 keratin expression, and the loss
of IRS as assessed by transglutaminase 1 and desmoglein labelling. IRS
distribution of heparanase and the induction of catagen-like involution
of hair follicles when a potent heparanase inhibitor is added suggest
that heparanase is a key actor of IRS differentiation and hair
homeostasis.

PMID: 18557927

J Biol Chem. 2006 Aug 18;281(33):23804-11. Epub 2006 Jun 20.
�
Characterization of mechanisms involved in secretion of active
heparanase.
Shafat I, Vlodavsky I, Ilan N.
Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty
of Medicine, Technion, Haifa 31096, Israel.

Heparanase is an endo-beta-D-glucuronidase involved in extracellular
matrix remodeling and degradation and implicated in tumor metastasis,
angiogenesis, inflammation, and autoimmunity. The enzyme is synthesized
as a latent 65-kDa protein and is processed in the lysosomal compartment
to an active 58-kDa heterodimer, where it is stored in a stable form. In
contrast, its heparan sulfate substrate is localized extracellularly,
suggesting the existence of mechanisms that trigger heparanase
secretion. Here we show that secretion of the active enzyme is mediated
by the protein kinase A and C pathways. Moreover, secretion of active
heparanase was observed upon cell stimulation with physiological
concentrations of adenosine, ADP, and ATP, as well as by the
noncleavable ATP analogue adenosine 5'-O-(thiotriphosphate). Indeed,
heparanase secretion was noted upon cell stimulation with a specific
P2Y1 receptor agonist and was inhibited by P2Y receptor antagonists. The
kinetics of heparanase secretion resembled the secretion of cathepsin D,
a lysosomal enzyme, indicating that the secreted heparanase is of
lysosomal origin. We suggest that secretion of active heparanase is
initiated by extracellular cues activating the protein kinase A and C
signaling pathways. The secreted enzyme(s) then facilitate cell invasion
associated with cancer metastasis, angiogenesis, and inflammation.

Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
* Research Support, U.S. Gov't, Non-P.H.S.

PMID: 16790442
 | 
Pages: 1
Prev: severe food allergies
Next: Is this allergic reaction or severe Asthma attack?